Substitution Reactions of Benzene and Its Derivatives • Benzene does not undergo electrophilic addition • It undergoes electrophilic aromatic substitution maintaining the aromatic core • Electrophilic aromatic substitution replaces a proton on benzene with another electrophile 1 electrophilic aromatic substitution 2 Electrophilic Aromatic Substitution 3 Halogenation of Benzene • Benzene’s electrons participate as a Lewis base in reactions with Lewis acids – Lewis acid: electron pair acceptor – Lewis base: electron pair donor • The product is formed by loss of a proton, which is replaced by a halogen 4 Bromination of Aromatic Rings • Benzene’s electrons participate as a Lewis base in reactions with Lewis acids • The product is formed by loss of a proton, which is replaced by bromine • FeBr3 is added as a catalyst to polarize the bromine reagent Br + Br FeBr3 2 + HBr 5 Bromine Polarization 6 Mechanism 1 • Diagram the mechanism for the bromination of benzene and note the formation of the carbocation: 7 Example 1 • Draw and name the three possible products of the bromination of toluene (not including HBr). 8 Chlorination of Aromatic Rings Cl + Cl FeCl3 2 + HCl Same mechanism as Br2 with FeBr3 9 Iodination of Aromatic Rings I2 I + HI CuCl2 •Iodine is unreactive towards aromatic rings •Oxidizing agents must be added to make reaction go (H2O2 or CuCl2) •Oxidizing agents oxidize I2 to a usable form (electrohphillic) that reacts as if it were I+ 10 Mechanism 2: Iodination of Aromatic Rings 2+ + + I2 + 2 Cu 2 I + 2 Cu I I2 + + I+ H I CuCl2 I + HI 11 Nitration of Aromatic Rings HNO3 NO2 H2O H2SO4 + Electrophile is the nitronium ion (NO2 ) Generated from HNO3 by protonation and loss of water 12 Mechanism 3: Nitration of Aromatic Rings • An electrophile must first be generated by treating concentrated nitric acid with concentrated sulfuric acid H + HSO H O NO2 + H2SO4 H O NO2 4 NO2 H2O nitronium ion 13 Mechanism 3: Nitration of Aromatic Rings • The nitronium electrophile is attacked by the benzene ring (nucleophile) + NO2 NO2 NO2 H2SO4 14 Sulfonation of Aromatic Rings SO2OH SO3 + H2O H2SO4 Fuming sulfuric acid – combination of SO3 and H2SO4 + Electrophile is HSO3 or SO3 Reaction is reversible Favored in forward direction with strong acid Favored in reverse direction with hot dilute aqueous acid 15 Mechanism 4: Sulfonation of Aromatic Rings H O O O + O S + H O S OH + O O S + O S OH O O O O O H O O S OH + + S H O O + O O S OH O SO3H + H2SO4 16 Conversion of sulfonic acids • Heating with NaOH at 300 ºC followed by neutralization with acid replaces the SO3H group with an OH o SO3H 1. NaOH, 300 OH 2.H3O No mechanism 17 Friedel-Crafts Reaction CH3 Cl CHCH3 + AlCl3 CH3CHCH3 + HCl benzene 2-chloropropane isopropylbenzene 18 Mechanism 5: Friedel-Crafts Reaction Cl AlCl3 + + HCl Cl AlCl3 + + - + Cl--AlCl3 + + H + - Cl--AlCl3 + HCl + AlCl3 19 Friedel-Crafts Reaction (Alkylation of Aromatic Rings) • the electrophile is a carbocation, R+ • only alkyl halides can be used – aryl halides and vinylic halides do not react. • will not occur on aromatic rings substituted by electron withdrawing substituents • can’t eat just one! It’s hard to stop after one substitution • skeletal rearrangements of the alkyl group often occur when using primary alkyl halides 20 Non-reactive 21 Ring Deactivators 22 Example 2: Friedel-Crafts Reaction • Diagram the mechanism for the electrophilic substitution of benzene by 2-chloropentane: 23 Friedel-Crafts Reaction • Multiple substitutions: – Reaction of benzene with 2-chloro- 2methylpropane. – Polyalkylation C(CH3)3 C(CH3)3 Cl AlCl + 3 + HCl CH3CCH3 CH3 C(CH3)3 Major product 24 Friedel-Crafts Reaction • Skeletal rearrangements in Friedel-Crafts reactions (hydride shift): – Will rearrange to form more stable carbocation intermediates Major product CH3 CHCH2CH3 CH3CH2CH2CH2Cl AlCl3 sec-Butylbenzene HCl + CH2CH2CH2CH3 Butylbenzene 25 Friedel-Crafts Reaction • Skeletal rearrangements in Friedel-Crafts reactions (alkyl shift): – Will rearrange to form more stable carbocation intermediates AlCl + Cl 3 HCl 1-Chloro-2,2- (1,1-Dimethylpropyl)- dimethylpropane benzene 26 Example 3: • Which of the following alkyl halides would you expect to undergo Friedel-Crafts reaction without rearrangement? – Chloroethane – 2-chlorobutane – 1-chloropropane – 1-chloro-2,2-dimethylpropane – Chlorocyclohexane 27 Friedel-Crafts Alkylation Summary • Only alkyl halides can be used!! • Will not occur on aromatic rings substituted by electron withdrawing substituents – Carbonyl and amino groups • Will have polyalkylation • Will have rearrangement to form more stable carbocation intermediate – Hydride shift or methyl shift • You need to know the mechanism!!! 28 Friedel-Crafts Acylation • Reaction of benzene with a carboxylic acid chloride, RCOCl in the presence of AlCl3 • Note: the acyl cation does not undergo rearrangement. It also is not prone to multiple substitutions. O O C AlCl3 CH2CH3 + CH3CH2CCl HCl 29 Friedel-Crafts Acylation • After acylation we can do a hydrogenation to get desired alkylated product AlCl3 HCl H2 Pd 30 Mechanism 6: Friedel-Crafts Acylation Acyl cation Cl AlCl3 + H C C+ 3 CH C O+ - O O 3 + Cl--AlCl3 O H C C+ 3 + O H + - Cl--AlCl3 O + HCl + AlCl3 31 Substituent Effects in Aromatic Rings • Substituents can cause a compound to be (much) more or (much) less reactive than benzene • Substituents affect the orientation of the reaction – the positional relationship is controlled – ortho- and para-directing activators, ortho- and para-directing deactivators, and meta- directing deactivators 32 33 34 Origins of Substituent Effects • An interplay of inductive effects and resonance effects • Inductive effect - withdrawal or donation of electrons through a bond (comparative electronegativity) • Resonance effect - withdrawal or donation of electrons through a bond due to the overlap of a p orbital on the substituent with a p orbital on the aromatic ring 35 Inductive Effects • Controlled by electronegativity and the polarity of bonds in functional groups • Halogens, C=O, CN, and NO2 withdraw electrons through bond connected to ring • Alkyl groups donate electrons 36 37 Resonance Effects – Electron Withdrawal • C=O, CN, NO2 substituents withdraw electrons from the aromatic ring by resonance • electrons flow from the rings to the substituents 38 Resonance Effects – Electron Donation • Halogen, OH, alkoxyl (OR), and amino substituents donate electrons • electrons flow from the substituents to the ring • Effect is greatest at ortho and para 39 Contrasting Effects • Halogen, OH, OR, withdraw electrons inductively so that they deactivate the ring • Resonance interactions are generally weaker, affecting orientation • The strongest effects dominate 40 • Activating An Explanation of Substituent Effects groups donate electrons to the ring, stabilizing the Wheland intermediate (carbocation) • Deactivating groups withdraw electrons from the ring, destabilizing the Wheland intermediate 41 42 Ortho- and Para-Directing Activators: Alkyl Groups • Alkyl groups activate: direct further substitution to positions ortho and para to themselves • Alkyl group is most effective in the ortho and para positions 43 44 Ortho- and Para-Directing Activators: OH and NH2 • Alkoxyl, and amino groups have a strong, electron-donating resonance effect • Most pronounced at the ortho and para positions 45 46 Ortho- and Para-Directing Deactivators: Halogens • Electron-withdrawing inductive effect outweighs weaker electron-donating resonance effect • Resonance effect is only at the ortho and para positions, stabilizing carbocation intermediate 47 48 Meta-Directing Deactivators • Inductive and resonance effects reinforce each other • Ortho and para intermediates destabilized by deactivation from carbocation intermediate • Resonance cannot produce stabilization 49 50 Summary Table: Effect of Substituents in Aromatic Substitution 51 52 Is it ortho/para or meta directing????? • All ortho- and para- directors have a lone pair of electrons on the atom directly attached to the ring (with the exception of alkyl, aryl, and CH=CHR groups). • All meta- directors have a positive charge or a partial positive charge on the atom attached to the ring. 53 In Summary: • All activating substituents are ortho/para directors • The weakly deactivating halogens are ortho/para directors • All other deactivating substituents are meta directors 54 CH3 Example 4: NO2 FeCl3 + Br2 Cl2 FeCl3 toluene nitrobenzene Br O C CH3 FeCl3 + Cl2 HNO3 H2SO4 bromobenzene benzaldehyde 55 Example 5: What product(s) would result from the nitration of each of the following compounds? • propylbenzene • benzenesulfonic acid • iodobenzene • benzaldehyde • cyclohexylbenzene • benzonitrile 56 Trisubstituted Benzenes: Additivity of Effects • If the directing effects of the two groups are the same, the result is additive 57 Substituents with Opposite Effects • If the directing effects of two groups oppose each other, the more powerful activating group decides the principal outcome • Usually gives mixtures of products 58 Meta-Disubstituted Compounds Are Unreactive • The reaction site is too hindered • To make aromatic rings with three adjacent substituents, it is best to start with an ortho-disubstituted compound 59 60 Example 6: OCH3 Br2 FeBr3 Br NH2 Br Br2 FeBr3 NO2 Cl Br2 FeBr3 61 Nucleophilic Aromatic Substitution • Aryl halides with electron-withdrawing substituents ortho and para react with nucleophiles • Form addition intermediate (Meisenheimer complex) that is stabilized by electron-withdrawal • Halide ion is lost Cl OH